Multiple myeloma is a plasma cell neoplasm that, despite recent advances, remains incurable and uniformly fatal. Recent advances in the understanding of the metabolism of malignant plasma cells have identified the autophagy pathway as an important mechanism of therapy resistance and therefore a potential therapeutic target. This proposarinvestigates the utility of adding autophagy inhibition to current effective therapies for myeloma. Proteasome inhibition using the novel agent bortezomib is now standard therapy for myeloma. The autophagy pathway is the major non-proteasomal mechanism for degradation of aggregated misfolded proteins and allows cells to escape the cytotoxic effects of proteasome inhibition, which makes combined inhibition an attractive strategy. Recent basic science laboratory work done by my collaborators has identified hydroxychloroquine as a potent inhibitor of autophagy in malignant cells. We have also shown that the addition of hydroxychloroquine to bortezomib results in synergistic killing of myeloma cells in vitro. These results justify investigation of the combination of hydroxychloroquine with bortezomib in patients with myeloma. Preclinical results have also identified the autophagy pathway as an important survival mechanism for malignant cells exposed to a wide variety of apoptotic stresses, including cytotoxic chemotherapy. The demonstration of increased autophagy in primary patient tumor cells after chemotherapy administration would justify a future trial of autophagy inhibition combined with cytotoxic chemotherapy. This research proposal therefore encompasses the following specific aims: (1) To determine, in a phase 1 clinical trial, the maximum tolerated dose of hydroxychloroquine when added to standard bortezomib therapy. (2) To determine, in a phase 2 trial, whether administration of hydroxychloroquine to patients with myeloma can inhibit autophagy in malignant cells and improve bortezomib efficacy. (3) To determine, in a prospective cohort study, whether administration of high-dose melphalan induces autophagy in malignant plasma cells purified from patient bone marrow samples. in addition, this Mentored Career Development Award is specifically intended to provide the Principal Investigator with comprehensive training in translational myeloma research to allow successful transition to an independent research career. RELEVANCE (See instructionsV. Multiple myeloma remains a deadly cancer that cannot be cured. This research seeks to improve two of the current most effective treatments for myeloma: autologous stem cell transplants and a newer medicine called bortezomib. The results will directly benefit patients with myeloma through a better understanding of how to increase the efficacy of current effective but insufficient treatments.